HIV requires its primary receptor, CD4, as well as additional cell surface molecules known as chemokine receptors, for entry into cells. These so-called co-receptors vary according to the tropism of the virus; macrophage tropic (M-tropic) viruses primarily utilize the beta-chemokine receptor CCR5, while T-cell tropic (T-tropic) viruses primarily use the alpha-chemokine receptor CXCR4. Dual-tropic virus (D-tropic) can enter cells after binding to either co-receptor. The beta-chemokines MIP-1alpha, MIP-1beta, and RANTES, which are CCR5 ligands, inhibit the entry of M-tropic viruses into CD4+ T cells. SDF-1, a ligand for CXCR4, inhibits T-tropic viral entry. In collaboration with Human Genome Sciences that has discovered 13 novel beta-chemokines and 3 alpha-chemokines, we investigated the possible activity of these agents in HIV disease utilizing several cellular and molecular systems. No single new chemokine inhibitor was found. However, there was some indication that combinations of the novel chemokines may have HIV-inhibitory effects. Several of the beta-chemokines substantially enhanced both M-tropic and D-tropic viruses. Future studies will focus on a careful delineation of these various activities.